Twenty years after a blood or marrow transplant (BMT), patients with adrenoleukodystrophy (ALD) and other metabolic disorders can have a greater than 70% survival rate, according to a new study. Still, disease progression remains the cause of most later deaths.
These findings were reported in the study “Late Mortality after Allogeneic Blood or Marrow Transplantation for Inborn Errors of Metabolism: A Report from the Blood or Marrow Transplant Survivor Study-2 (BMTSS-2),” published in the journal Biology of Blood and Marrow Transplantation.
Allogeneic BMT, a procedure that replaces blood-forming cells with cells from a genetically similar donor, is used to treat people with ALD and other metabolic disorders such as Hurler syndrome and metachromatic leukodystrophy (MLD) with the goal of stopping or slowing disease progression.
Studies have looked at survival outcomes after allogeneic BMT in these patients, but a comprehensive assessment of mortality is lacking. Aiming to address this gap, a team from the U.S. and Sweden analyzed data provided by the Blood or Marrow Transplant Survivor Study-2 (BMTSS-2), a collaboration between the City of Hope, the University of Minnesota, and the University of Alabama at Birmingham.
Data on a total of 273 patients were included. All underwent allogeneic BMT between 1983 and 2014, and survived two years or longer after the procedure — the first two years post-transplant being key to overall survival. ALD was the most frequent disorder, in 102 patients (37.4%), 96 patients (35.2%) had Hurler syndrome, 28 (10.2%) had MLD, and 47 (17.2%) had other disorders associated with inborn errors of metabolism.
The median age at BMT was 4.9 years. Overall, 189 patients (69.2%) were male, 233 (85.3%) were non-Hispanic whites, 192 (70.3%) received cells from an unrelated donor, and 121 (44.3%) were given a cord blood transplant.
Cyclophosphamide was used in the preparative regimen for the transplant in 228 patients (83.5%), busulfan in 194 (71.1%), and total body irradiation in 111 (40.7%). In turn, cyclosporine was the most frequently used agent as a prophylaxis for graft-versus-host disease (GVHD) — an attack of the host’s cells by transplanted stem cells – given to 255 patients (93.4%).
Results showed that 54 people died after a median follow-up of 10.5 years, resulting in overall survival rates of 92.8% at five years, 85.5% at 10 years, and 73.5% at 20 years. Median age at death was 13.8 years.
Data further showed that the mortality rate dropped as time from the procedure increased, as shown by 7 patients (12.9%) dying at 21 years or longer after BMT, compared to 22 (40.7%) within two to five years after the procedure.
In the 47 patients whose cause of death was known, most were due to the primary disease (76%). Other causes included malignant tumors (4%), infection (2%), cardiac disease (2%), and pulmonary disease (2%). Disease-related mortality at 20 years (19.7%) was higher than that of transplant-related mortality (3.9%).
Overall, the patients showed a 29-fold greater risk of premature death compared to the general U.S. population, which dropped to a 9-fold greater risk at 20 years after BMT. Standardized mortality ratio — a ratio of observed to expected deaths — declined with time after BMT.
The type of donor, preparative regimen, and GVHD prophylaxis of ALD patients were similar to that of the overall patient population. Ten (9.8%) had chronic GVHD.
Thirteen ALD patients died after a median follow-up of 7.8 years, leading to an overall post-BMT survival rate of 94.3% at five years and 86.6% at 10 years. Use of immune T-cell depleted grafts and undergoing transplant after 2010 were significantly link with a greater risk of late mortality. In turn, younger age at BMT, and having an unrelated donor suggested a protective effect on late mortality.
All deaths in the eight ALD patients with known cause were directly attributable to their primary disease, with pulmonary disease being the secondary cause of death in five cases.
Patients with Hurler syndrome were younger at the time of the transplant (median age, 1.5 years) than those with ALD (8.6 years) or MLD (9.8 years). Fourteen Hurler syndrome patients died after a median follow-up of 13.2 years, resulting in an overall survival of 96.6% at five years and 93.8% at 10 years post-transplant.
As in people with ALD, BMT at a younger age correlated with a lower risk of all-cause late mortality in Hurler syndrome patients. Use of busulfan and cyclosporine were also protective. Primary disease progression was again the most prevalent cause of mortality (10 patients, 71%).
Patients with MLD had the longest follow-up (mean of 15.6 years). The overall survival was 92.9% at five years and 81.7% at 10 years. All deaths were due to the primary disease.
“Our data show that patients with [metabolic disorders] who undergo allogeneic BMT and survive for at least 2 years have a relatively favorable overall survival even at 20 years after BMT,” the researchers concluded.
“These findings provide important information for the families and the healthcare providers caring for these patients,” the team added.